Spital Square was started in 1733 - Robert Seymour’s edition of Stow’s Survey of London re marked that "in place of this hospital (St. Mary Spital), ... are now built many handsome houses for merchants and others".

Spital Square was mainly a residential area. The houses were mostly occupied originally by silk merchants and master weavers, rather than by working weavers. In 1751 it was said that there were twelve coaches kept in Spital Square, two by weavers and the rest by silk merchants and brokers. At least nine of the thirteen Spitalfields silk manufacturers who in 1828 resolved not to grant an advance of wages to weavers on strike lived in the Square. Tallis described the Square in about 1838–9 as ’a small quadrangle consisting of respectable private residences and wholesale warehouses … mostly in the Silk trade’ In 1842 it was described as mainly inhabited by silk manufacturers, ’the humble operatives living for the most part eastward of this spot’. Nine of the fourteen trustees for the Norton Folgate almshouses in 1851 were residents in the Square. The establishment of a girls’ school in the Square in 1891 probably indicates the end of its residential attractions but some measure of quiet was preserved until the 1914–18 war by its freedom from through-traffic.

In the eighteenth century the seclusion and quiet of the Square was preserved, despite its proximity to Spitalfields Market and Bishopsgate Street. In 1775 an extra watchman was employed by the Liberty of Norton Folgate to patrol the northern arm of the Square. The privacy of the Square was, however, chiefly maintained by the obstacles to through-traffic There was only a comparatively narrow entry, nineteen feet wide, from Bishopsgate Street, while bars or bollards at the northern and eastern ends of the Square prevented the entry of wheeled vehicles from Folgate Street and Lamb Street.

The provision of easier access to the extended market through the southern part of the Square was completed in 1929 by the widening of the western entrance to the Square from Bishopsgate Street from nineteen feet to forty-eight feet. The bollards and gate at the north end of the Square, opening on Folgate Street, were removed in 1931.

The houses on the north and south sides of the eastern arm of Spital Square, together with No. 21, were purchased between 1921 and 1927 by the Corporation of London under powers granted them for the extension of Spitalfields Market, and pulled down to widen the street. The demolition of the south side was in progress in 1922. The demolition of the north side was completed by 1929.

The houses on the north side of the western arm and the west side of the northern arm were demolished in the early 1930s for the site of the Co-operative Wholesale Society Fruit Warehouse, built in 1935–6.

The name Spitalfields appears in the form Spittellond in 1399; as The spitel Fyeld on the 16th-century Civitas Londinium map associated with Ralph Agas. The land belonged to St Mary Spital, a priory or hospital erected on the east side of the Bishopsgate thoroughfare in 1197, and the name is thought to derive from this. An alternative, and possibly earlier, name for the area was Lolsworth.

After the revocation of the Edict of Nantes, Spitalfields was inhabited by prosperous French Huguenot silk weavers. In the early 19th century their descendants were reduced to a deplorable condition due to the competition of the Manchester textile factories and the area began to deteriorate into crime-infested slums. The spacious and handsome Huguenot houses were divided up into tiny dwellings which were rented by poor families of labourers, who sought employment in the nearby docks.